This invention relates to organic compounds and compositions which have useful therapeutic properties. More particularly, the invention concerns novel discodermolide compounds having immunomodulatory and antitumor activities, pharmaceutical compositions comprising such compounds, and methods of their use for therapeutic purposes. Another aspect of the present invention pertains to the identification of regions of the discodermolide molecule which are responsible for certain aspects of the bioactivity of discodermolide.
Of great importance to man is the control of pathological cellular proliferation such as that which occurs in the case of cancer. Considerable research and resources have been devoted to oncology and antitumor measures including chemotherapy. While certain methods and chemical compositions have been developed which aid in inhibiting, remitting, or controlling the growth of, for example, tumors, new methods and antitumor chemical compositions are needed.
In searching for new biologically active compounds, it has been found that some natural products and organisms are potential sources for chemical molecules having useful biological activity of great diversity. For example, the diterpene commonly known as Taxol, isolated from several species of yew trees, is a mitotic spindle poison that stabilizes microtubules and inhibits their depolymerization to free tubulin (Fuchs, D. A., R. K. Johnson [1978] Cancer Treat. Rep. 62:1219-1222; Schiff, P. B., J. Fant, S. B. Horwitz [1979] Nature (London) 22:665-667). Taxol is also known to have antitumor activity and has undergone a number of clinical trials which have shown it to be effective in the treatment of a wide range of cancers (Rowinski, E. K. R. C. Donehower [1995] N. Engl. J Med. 332:1004-1014). See also, e.g., U.S. Pat. Nos. 5,157,049; 4,960,790; and 4,206,221.
Marine sponges have also proven to be a source of biologically active chemical molecules. A number of publications disclose organic compounds derived from marine sponges including Scheuer, P. J. (ed.) Marine Natural Products, Chemical and Biological Perspectives, Academic Press, New York, 1978-1983, Vol. I-V; Uemura, D., K. Takahashi, T. Yamamoto, C. Katayama, J. Tanaka, Y. Okumura, Y. Hirata (1985) J. Am. Chem. Soc. 107:4796-4798; Minale, L. et al. (1976) Fortschr. Chem. org. Naturst. 33:1-72; Faulkner, D. J. (1998) Natural Products Reports 15:113-158; Gunasekera, S. P., M. Gunasekera, R. E. Longley and G. K. Schulte (1990) xe2x80x9cDiscodermolide: A new bioactive polyhydroxy lactone from the marine sponge Discodermia dissolutaxe2x80x9d J. Org. Chem., 55:4912-4915 [correction (1991) J. Org. Chem. 56:1346]; Hung, Deborah T., Jenne B. Nerenberg, Stuart Schreiber (1994) xe2x80x9cDistinct binding and cellular properties of synthetic (+)- and (xe2x88x92) discodermolidesxe2x80x9d Chemistry and Biology 1:67-71; Hung, Deborah T., Jie Cheng, Stuart Schreiber (1996) (+)-Discodermolide binds to microtubules in stoichiometric ratio to tubulin dimers, blocks Taxol binding and results in mitotic arrestxe2x80x9d Chemistry and Biology 3:287-293; Nerenberg, Jennie B., Deborah T. Hung, Patricia K. Somers, Stuart L. Schreiber (1993) xe2x80x9cTotal synthesis of immunosuppressive agent (xe2x88x92)-discodermolidexe2x80x9d J. Amer. Chem. Soc. 115:12621 -12622; Smith III, Amos B., Yuping Qiu, David R. Jones, Karoru Kobayashi (1995) xe2x80x9cTotal synthesis of (xe2x88x92) discodernolidexe2x80x9d J. Amer. Chem. Soc. 117:12011-12012; Harried, Scott H., Ge Yang, Marcus A. Strawn, David C. Myles (1997) xe2x80x9cTotal synthesis of (xe2x88x92)-discodermolide: an application of a chelation-controlled alkylation reactionxe2x80x9d J. Org. Chem. 62:6098-6099; Balachandran, R., ter Haar, E., Welsh, M. J., Grant, S. G., and Day, B. W. (1998) xe2x80x9cThe potent microtubule-stabilizing agent (+)-discodermolide induces apoptosis in human breast carcinoma cells-preliminary comparisons to paclitaxel.xe2x80x9d Anticancer Drugs 9: 67-76 and references cited therein. U.S. Pat. No. 4,808,590 discloses compounds, having antiviral, antitumor, and antifungal properties, isolated from the marine sponge Theonella sp. (International Patent Application No. WO 9824429; Kowalski, R. J., P. Giannakakou, S. P. Gunasekera et al. (1997) Mol. Pharmacol 52:613-622; ter Haar, E., R. J. Kowalski, E. Hamel et al. (1996) Biochemistry 35:243-250; Stafford, J. A. and M. M. Mehrotra (1995) Chemtract: Org. Chem. 8:41-47; and U.S. Pat. No. 5,789,605.
A principal object of the subject invention is the provision of novel compositions of biologically active discodermolide analogs which can advantageously be used for immunomodulation and/or treating cancer. The compounds of the subject invention have utility for use in the treatment of cancer, and as tubulin polymerizers and as microtubule stabilization agents.
In a specific embodiment, the novel compositions and methods of the subject invention can be used in the treatment of an animal hosting cancer cells including, for example, inhibiting the growth of tumor cells in a mammalian host. More particularly, the subject compounds can be used for inhibiting in a human the growth of tumor cells, including cells of breast, colon, CNS, ovarian, renal, prostate, liver, pancreatic, uterine, or lung tumors, as well as human leukemia or melanoma cells. The mechanisms for achieving anticancer activity exhibited by the subject compounds would lead a person of ordinary skill in the art to recognize the applicability of the subject compounds, compositions, and methods to additional types of cancer as described herein.
The subject invention provides new analogs of discodermolide which, advantageously, possess useful biological activity against tumors and other forms of cancer. Another aspect of the present invention pertains to the identification of regions of the discodermolide molecule which are responsible for certain aspects of the bioactivity of discodermolide.
In specific embodiments, the subject invention provides four new analogs of discodermolide isolated from nature and nine new analogs of discodermolide produced through organic synthesis. The compounds of the subject invention have not been isolated previously from a natural source nor have they been previously synthesized. These compounds indicate the effects on biological activity caused by 1) modification of functionality located at the lactone end of the molecule; 2) reduction of selected double bonds present in the molecule and 3) the contribution of the carbamate functionality towards the biological activity.
Included in these embodiments are analogs which can be prepared through modifications to five regions ofthe discodermolide molecule, those being 1) the C-1 through C-7 lactone and connector region, 2) the C-8 through C-15 first hairpin, 3) the C-16 through C-20 second hairpin, 4) the C-21 through C-24 diene and 5) the carbamate at C-19. The activity of the compounds vary according to the region(s) modified. The structure activity data promotes the C-8 through C-15 and C-16 through C-20 hairpin regions as critical to the activity of the discodermolide molecule by providing an optimal spatial relationship between the C-11 hydroxyl and the C-17 hydroxyl functionalities found in natural and synthetic analogs which are essential for induction of tubulin polymerization and stabilizing of the microtubule network, thus causing a block in the cell cycle at the G2/M checkpoint. In addition, the C-1 though C-7 lactone and connector region provide a hydrogen bond acceptor such as a carbonyl group and the C-21 through C-24 diene region serve to provide a hydrophobic group; both functionalities being positioned in the same spatial relationship to the C-11 and C-17 hydroxyl groups as is found in discodermolide and active analogs.
In accordance with the subject invention, methods for inhibiting cancer cells in a host include contacting tumor cells with an effective amount of the new pharmaceutical compositions of the invention. The cancer cells inhibited by the invention are those which are susceptible to the subject compounds described herein or compositions comprising those compounds.
Additional aspects of the invention include the provision of methods for producing the new compounds and compositions.
Other objects and further scope of applicability of the present invention will become apparent from the detailed descriptions given herein; it should be understood, however, that the detailed descriptions, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent from such descriptions.